Gene Therapy for Lymphoma in HIV Patients

Recruiting at 3 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AIDS Malignancy Consortium

Must be taking: Anti-HIV regimen

Disqualifiers: Active CNS disease, Myeloproliferative disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 8

11 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of gene therapy in treating patients with human immunodeficiency virus (HIV)-related lymphoma that did not respond to therapy or came back after an original response receiving stem cell transplant. In gene therapy, small stretches of deoxyribonucleic acid (DNA) called "anti-HIV genes" are introduced into the stem cells in the laboratory to make the gene therapy product used in this study. The type of anti-HIV genes and therapy in this study may make the patient's immune cells more resistant to HIV-1 and prevent new immune cells from getting infected with HIV-1.

Will I have to stop taking my current medications?

Participants must switch from zidovudine (AZT) and efavirenz to an alternative HIV regimen at least two weeks before the transplant. Other medications are not specifically mentioned, so it's best to discuss with the study team.

What data supports the effectiveness of the treatment Gene Therapy for Lymphoma in HIV Patients?

Research shows that gene-modified hematopoietic stem cells can provide HIV-resistant immune cells, potentially offering a long-term remission of HIV/AIDS. In clinical trials, these gene-modified cells have been safely engrafted in patients, showing persistent expression of anti-HIV genes, which supports the development of this treatment for HIV-associated lymphoma. ^{1 2 3 4 5}

Is gene therapy for lymphoma in HIV patients safe?

Research shows that gene therapy using modified stem cells has been tested in both mice and humans, showing no significant adverse effects. Studies indicate that this approach is generally safe, with successful engraftment and normal development of immune cells. ^{2 5 6 7 8}

How is the treatment for lymphoma in HIV patients unique?

This treatment is unique because it uses gene therapy to modify a patient's own stem cells to resist HIV, potentially providing a long-term solution without daily medication. It involves a lentivirus vector that delivers a combination of genetic modifications to the patient's stem cells, making them resistant to HIV and allowing them to develop into various immune cells that can fight infections. ^{3 5 9 10 11}

Research Team

Mehrdad Abedi

Principal Investigator

AIDS Malignancy Consortium

Eligibility Criteria

Adults over 18 with HIV-related lymphomas that have relapsed or didn't respond to treatment, who are now receiving a stem cell transplant. They must be on stable antiretroviral therapy, have good organ function and performance status, and agree to use contraception. Excluded are those with severe health issues like dementia, uncontrolled infections, recent heart problems, or other cancers.

Inclusion Criteria

My kidney function, measured by creatinine, is within normal limits.

You are expected to live for at least 3 more months.

I have a confirmed diagnosis of Hodgkin's lymphoma within the last 8 months.

Exclusion Criteria

I do not have any active infections.

I haven't had heart issues like heart attack, irregular heartbeat, or heart failure in the last 6 months.

I have had a seizure in the last year.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-transplant Conditioning

Patients receive BEAM or BEAM-R regimen as standard of care, including carmustine, cytarabine, etoposide, and melphalan, with rituximab for B-cell lymphoma patients.

6 days

Daily visits for chemotherapy administration

Transplant and Gene Therapy

Patients undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells.

1 day

1 visit (in-person)

Post-transplant Monitoring

Patients are monitored for engraftment and safety, including hematologic function and CD4 recovery.

3 months

Frequent visits at days 7, 14, 21, 28, 42, 60, 90

Long-term Follow-up

Participants are monitored for safety, efficacy, and persistence of gene-modified cells, with assessments up to 15 years.

15 years

Yearly visits after initial frequent follow-ups

Treatment Details

Interventions

• Autologous Hematopoietic Stem Cell Transplantation
• Carmustine
• Cytarabine
• Etoposide
• Laboratory Biomarker Analysis
• Lentivirus Vector CCR5 shRNA/TRIM5alpha/TAR Decoy-transduced Autologous CD34-positive Hematopoietic Progenitor Cells
• Melphalan
• Peripheral Blood Stem Cell Transplantation

Trial Overview The trial is testing gene therapy using 'anti-HIV genes' in stem cells for patients with HIV-related lymphoma undergoing stem cell transplants. The aim is to make immune cells resistant to HIV-1 infection. It includes lab analysis of biomarkers and various chemotherapy drugs alongside the transplantation procedure.

Participant Groups

Group I: Treatment (anti-HIV gene transduced CD34+ cells) Experimental Treatment 8 Interventions

Patients receive BEAM regimen administered as standard of care comprising carmustine on day -6, cytarabine BID on days -5 to -2, etoposide BID on days -5 to -2, and melphalan on day -1. Patients undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells over 1 hour.

Who Is Running the Clinical Trial?

AIDS Malignancy Consortium

Lead Sponsor

Trials

64

Recruited

9,600+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

References

1. United States pubmed.ncbi.nlm.nih.gov

RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Safety of CD34+ Hematopoietic Stem Cells and CD4+ T Lymphocytes Transduced with LVsh5/C46 in HIV-1 Infected Patients with High-Risk Lymphoma. [2020]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Stem cell-based therapies for HIV/AIDS. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Phase I/II Clinical Trials Using Gene-Modified Adult Hematopoietic Stem Cells for HIV: Lessons Learnt. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Generation of an HIV-1-resistant immune system with CD34(+) hematopoietic stem cells transduced with a triple-combination anti-HIV lentiviral vector. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

A clinical trial of retroviral-mediated transfer of a rev-responsive element decoy gene into CD34(+) cells from the bone marrow of human immunodeficiency virus-1-infected children. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Hematologic recovery in mice transplanted with bone marrow stem cells expressing anti-human immunodeficiency virus genes. [2012]

8. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of a tCD25 preselective combination anti-HIV lentiviral vector in human hematopoietic stem and progenitor cells. [2015]

9. United States pubmed.ncbi.nlm.nih.gov

Stable Delivery of CCR5-Directed shRNA into Human Primary Peripheral Blood Mononuclear Cells and Hematopoietic Stem/Progenitor Cells via a Lentiviral Vector. [2018]

10. England pubmed.ncbi.nlm.nih.gov

CXCR4 and CCR5 shRNA transgenic CD34+ cell derived macrophages are functionally normal and resist HIV-1 infection. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Robust and efficient regulation of transgene expression in vivo by improved tetracycline-dependent lentiviral vectors. [2021]